Breathing is a complex repetitive behavior in which a centrally generated rhythm is translated into a synergistic pattern of motor output on nerves arising from cranial, cervical, thoracic and lumbar levels. The precise spatiotemporal pattern of activity differs markedly on the diverse motor nerves and can increase in magnitude on some while simultaneously decreasing on others. This proposal is for a series of studies aimed at addressing the distribution of rhythm versus pattern generating roles within the circuitry generating and controlling respiratory motor output. The working hypothesis is that timing and pattern are generated by different neurons within anatomically separated brainstem regions. To test this hypothesis, a series of electrophysiological, neuroanatomical and pharmacological techniques will be employed. The differential localization of rhythm and pattern generating circuitry will be tested by interrupting neural activity irreversibly with electrolytic lesions or injection of agents that inhibit neuronal activity. A potential role for neurons within specific regions in generating respiratory rhythm or pattern will be inferred if: 1) unilateral interruption of neuronal activity selectively blocks reflex changes in respiratory timing or pattern, and 2) bilateral interruption of activity within these regions abolishes respiratory rhythm generation. The source of afferent neuronal input to regions containing neurons potentially involved in rhythm or pattern generation will initially be examined using fluorescent double labeling techniques. It is hypothesized that regions involved in rhythm generation will exhibit the extensive synaptic interactions required for coordination of activity between bilaterally distributed rhythm generating networks. Within regions meeting these criteria, the activity patterns and synaptic drive of neurons activated during reflexive changes in respiratory rhythm or pattern will be determined using intracellular and extracellular recording. Responses of individual neurons will be correlated with changes in rhythm and pattern. The underlying premise is that neurons having a causal role in respiratory rhythm will exhibit discharge patterns that maintain a fixed relationship to respiratory rhythm. The axonal projection patterns and post-synaptic connections will be determined for neurons, which are identified as candidates for mediating the Breuer-Hering reflex. Identification of the neuronal pathways producing respiratory rhythm and pattern are prerequisite for full understanding of a variety of clinical disorders such as sleep apnea and central hypoventilation syndrome.